Inhibition of Resistant Variants of HIV Protease The AIDS epidemic encompasses more than 30 million people infected with HIV. Patient outcomes were improved dramatically by highly active antiretroviral therapy including inhibitors of the vira protease. No cure exists, however, and the long term effectiveness of current AIDS therapy is confronted by the challenge of rapid evolution of drug- resistant HIV. Hence, there is urgent need for new therapies to overcome the problem of drug-resistance. The potent drug darunavir targets resistant protease variants, and our crystal structures defined how darunavir binds HIV protease. Despite darunavir's high potency, resistance has arisen in the clinic to all current drugs. The appearance of new resistance mutations, diverse resistance mechanisms and adverse side effects necessitate the development of novel inhibitors to expand the repertoire and potency of antiviral agents for resistant HIV. Our studies of structures and activities of protease mutants have identified distinct molecular mechanisms for resistance including mutations that: 1) decrease protease interactions with inhibitors;2) decrease the enzyme stability;or 3) increase the flap mobility. These insights and the strategy of incorporating more interactions with the protease backbone have led to a series of novel antiviral inhibitors with excellent potency for resistant HIV. During this project period we have identified a unique resistance mechanism due to mutation L76V and discovered extremely resistant protease variants that evade inhibition at the autoprocessing stage, unlike the wild type protease precursor. Our X-ray structures have guided the design of novel inhibitors with 10-fold greater antiviral potency than darunavir for resistant viral strains, as well as inhibitors 10-fold more effective than darunavir against highly resistant proteases. Our proposed studies will focus on discovery of the unique molecular mechanisms for high level resistance to protease inhibitors and the application of these insights to design the next generation of antiviral inhibitors. These multidisciplinary studies leverage the expertise, unique resources and novel approaches developed in the PIs groups together with an established set of collaborators to integrate computational, X-ray crystallographic, biochemical and biophysical techniques with inhibitor design, chemical synthesis, and virology studies. The expected outcomes will be 1) accurate predictions for resistance, 2) discovery of novel and conserved molecular mechanisms for resistance, and 3) new antiviral inhibitors for resistant HIV infections.

Public Health Relevance

A major challenge limiting success of HIV/AIDS therapy is the rapid development of viral strains with resistance to drugs. Knowledge of the relationships between sequence, structure and activities of HIV protease variants with drug resistant mutations will be applied to predict resistance and develop new antiviral agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01GM062920-16S2
Application #
8928384
Study Section
Special Emphasis Panel (ZRG1-AARR-E (81))
Program Officer
Barski, Oleg
Project Start
1997-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
16
Fiscal Year
2014
Total Cost
$43,256
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Ghosh, Arun K; Brindisi, Margherita; Nyalapatla, Prasanth R et al. (2017) Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. Bioorg Med Chem 25:5114-5127
Weber, Irene T; Harrison, Robert W (2017) Decoding HIV resistance: from genotype to therapy. Future Med Chem 9:1529-1538
Gerlits, Oksana; Keen, David A; Blakeley, Matthew P et al. (2017) Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K. J Med Chem 60:2018-2025
Ghosh, Arun K; Sean Fyvie, W; Brindisi, Margherita et al. (2017) Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. Bioorg Med Chem Lett 27:4925-4931
Ghosh, Arun K; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R et al. (2017) Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. J Med Chem 60:4267-4278
Ghosh, Arun K; Osswald, Heather L; Glauninger, Kristof et al. (2016) Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation. J Med Chem 59:6826-37
Gerlits, Oksana; Wymore, Troy; Das, Amit et al. (2016) Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site. Angew Chem Int Ed Engl 55:4924-7
Park, Joon H; Sayer, Jane M; Aniana, Annie et al. (2016) Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme. Biochemistry 55:2390-400
Weber, Irene T; Harrison, Robert W (2016) Tackling the problem of HIV drug resistance. Postepy Biochem 62:273-279
Shen, ChenHsiang; Yu, Xiaxia; Harrison, Robert W et al. (2016) Automated prediction of HIV drug resistance from genotype data. BMC Bioinformatics 17 Suppl 8:278

Showing the most recent 10 out of 37 publications